In healthy subjects, the heart rate demonstrates predictable, phasic changes with respiration and blood pressure. This phenomenon, known as sinus arrhythmia (SA), reflects the interaction between ongoing perturbations to the cardiovascular system and the response of its regulatory system. We hypothesize that with the onset of diseases that disrupt the cardiovascular system or its regulatory system, normal SA may be altered. We have developed phase response curves (PRCs) as a means of characterizing SA and have detected phase locking between the oscillations of the lung and the heart. We propose that healthy, innervated subjects, as well as non-rejecting heart transplant recipients demonstrate predictable, phasic changes in heart rate with respiration and blood pressure and show phase locking; and that this predictable response is altered with the onset of acute rejection and restored once the rejection resolves. We will characterize SA by altering the subject's respiratory frequency and tidal volume and observing the effects of these perturbations on PRCs. The testing protocol includes measurement during spontaneous respiration, metronome- and heart-synchronized breathing, and breathing at various tidal volumes. We will test for phase locking by continuously increasing the respiratory rate over various frequencies and studying the results on PRCs. We will establish norms for innervated controls and non-rejecting heart transplant recipients. Next, we will correlate the PRCs with results of endomyocardial biopsy (EMBx) to see if PRCs are a sensitive means of detecting acute rejection. At present, detecting rejection in heart transplant recipients requires EMBx, an invasive procedure that adds significantly to patient cost and discomfort. The goal of the project is to develop an inexpensive, out-patient test for diagnosing acute rejection.